HRP20000893A2 - Novel 17-halogenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same - Google Patents

Novel 17-halogenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same Download PDF

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HRP20000893A2
HRP20000893A2 HR20000893A HRP20000893A HRP20000893A2 HR P20000893 A2 HRP20000893 A2 HR P20000893A2 HR 20000893 A HR20000893 A HR 20000893A HR P20000893 A HRP20000893 A HR P20000893A HR P20000893 A2 HRP20000893 A2 HR P20000893A2
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beta
phenyl
estra
ethoxy
alpha
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Yasmina Bouali
Jacques Mauger
Francois Nique
Patrick Van De Velde
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Hoechst Marion Roussel Inc
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    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
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    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

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Description

Ovaj izum se odnosi na nove 17-halogenirane 19-nor steroidne spojeve, postupak njihove priprave i međuprodukte, njihovu upotrebu kao lijekova, te farmaceutske kompozicije koje ih sadrže. This invention relates to new 17-halogenated 19-nor steroid compounds, their preparation process and intermediates, their use as drugs, and pharmaceutical compositions containing them.

Osteoporoza je patologija koju karakterizira kvantitativna i kvalitativna redukcija koštane tvari, dovoljna da bi na spontan način ili u slučajevima s minimalnom traumom dovela do kralježnične ili periferne frakture. Premda je pojava te bolesti rezultat brojnih faktora, menopauza kod žena čini dominantni faktor gubitka kosti ili osteopenije. Osteoporosis is a pathology characterized by a quantitative and qualitative reduction of bone substance, sufficient to lead to a vertebral or peripheral fracture spontaneously or in cases with minimal trauma. Although the appearance of this disease is the result of numerous factors, menopause in women is the dominant factor in bone loss or osteopenia.

Ta osteopenija se manifestira prorjeđivanjem i modifikacijom spužvaste građe kostiju, posljedica čega je porast krtosti kostura i rizik frakture. Gubitak kosti se jako povećava nakon menopauze zbog supresije funkcije jajnika i prije nego li uspori nakon navršenih 65 godina starosti doseže 3 do 5% godišnje. This osteopenia is manifested by the thinning and modification of the spongy structure of the bones, the consequence of which is an increase in the fragility of the skeleton and the risk of fracture. Bone loss increases greatly after menopause due to suppression of ovarian function and before slowing down after the age of 65 reaches 3 to 5% per year.

Za terapeutske svrhe, hormonalni manjak nakon menopauze se može kompenzirati primjenom terapije hormonske zamjene, pri čemu estrogen ima glavnu ulogu u očuvanju koštane mase. Međutim, dugotrajna estrogenska terapija je ponekad povezana s neželjenim efektima na genitalnom aparatu (endometrijalna hiperplazija, tumor dojke ...), što čini glavni razlog unazađenju i ograničava njenu upotrebu. For therapeutic purposes, hormonal deficiency after menopause can be compensated by the use of hormone replacement therapy, where estrogen plays a major role in preserving bone mass. However, long-term estrogen therapy is sometimes associated with unwanted effects on the genital apparatus (endometrial hyperplasia, breast tumor...), which is the main reason for regression and limits its use.

Zbog toga je poželjno naći spojeve različite od estradiola koji posjeduju razdvojenu estrogensku aktivnost, naime kod kojih se javlja estrogenska aktivnost na nivou kostiju, ali koji ne pokazuju ili imaju malu aktivnost endometrijalne hiperplazije, a također nisu aktivni u proliferaciji tumora dojke. For this reason, it is desirable to find compounds different from estradiol that have a separate estrogenic activity, namely, in which estrogenic activity occurs at the bone level, but which do not show or have little endometrial hyperplasia activity, and are also not active in the proliferation of breast tumors.

Zbog toga su predmet ovog izuma spojevi prikazani općom formulom (I): Therefore, the subject of this invention are the compounds shown by the general formula (I):

[image] [image]

kod kojih: in which:

R1 predstavlja vodikov atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk ili (CO)-Alk radikal, R1 represents a hydrogen atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk or (CO)-Alk radical,

R2 predstavlja radikal dobiven od ravnog ili razgranatog, zasićenog ili nezasićenog ugljikovodika koji sadrži 1 do 6 ugljikovih atoma R2 represents a radical obtained from a straight or branched, saturated or unsaturated hydrocarbon containing 1 to 6 carbon atoms

X predstavlja atom halogena, X represents a halogen atom,

Y predstavlja jednostruku vezu, O, NH, S, SO, ili SO2, Y represents a single bond, O, NH, S, SO, or SO2,

Z predstavlja vodikov atom ili halogeni atom, Z represents a hydrogen atom or a halogen atom,

n je jednak brojevima 2, 3, 4 ili 5, n is equal to the numbers 2, 3, 4 or 5,

R3 i R4, identični ili različiti, predstavljaju vodikov atom, (CH2)m’-Ar, (CH2)m’-Het ili (CH2)m’-Alk skupinu, ili R3 i R4 tvore zajedno s dušikovim atomom, s kojim su povezani, aromatski ili nearomatski, zasićeni ili nezasićeni mono- ili policiklički heterocikl s 3 do 15 članova koji po volji sadrže 1 do 3 dodatna hetero atoma izabrana između kisika, sumpora i dušika, nesupstituirani ili supstituirani, R3 and R4, identical or different, represent a hydrogen atom, (CH2)m'-Ar, (CH2)m'-Het or (CH2)m'-Alk group, or R3 and R4 form together with a nitrogen atom, with which they are linked, aromatic or non-aromatic, saturated or unsaturated mono- or polycyclic heterocycle with 3 to 15 members optionally containing 1 to 3 additional hetero atoms selected from oxygen, sulfur and nitrogen, unsubstituted or substituted,

Ar predstavlja karbocikličku arilnu skupinu koja sadrži 6 do 18 ugljikovih atoma, Het predstavlja zasićeni ili nezasićeni aromatski ili nearomatski heterocikl koji sadrži od 1 do 9 ugljikovih atoma i od 1 do 5 heteroatoma odabranih između atoma kisika, dušika ili sumpora, Alk predstavlja radikal dobiven iz zasićenog ili nezasićenog, linearnog, razgranatog ili cikličkog, nearomatskog ugljikovodika i sadrži od 1 do 12 uglikovih atoma, radikali Ar, Het ili Alk mogu biti supstituirani ili nesupstituirani, m i m’ predstavljaju brojeve 0, 1, 2 ili 3, crtkane linije predstavljaju moguću dvostruku vezu, kao i njihove soli s dodanim bazama ili kiselinama. Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, Het represents a saturated or unsaturated aromatic or non-aromatic heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, Alk represents a radical obtained from saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon and contains from 1 to 12 carbon atoms, radicals Ar, Het or Alk can be substituted or unsubstituted, m and m' represent the numbers 0, 1, 2 or 3, dashed lines represent a possible double bond, as well as their salts with added bases or acids.

Pod halogenom se podrazumijeva: jod, brom, klor ili fluor. Halogen means: iodine, bromine, chlorine or fluorine.

Na položaju 4 je preferirano klor ili brom. Chlorine or bromine is preferred at position 4.

Na položaju 17 je preferirano fluor. Fluorine is preferred at position 17.

Pod (CH2)m, (CH2)m’ se podrazumijevaju slijedeće vrijednosti: jednostruka veza u slučaju kada je m jednak 0, CH2, (CH2)2 i (CH2)3. The following values are understood by (CH2)m, (CH2)m': single bond in the case when m is equal to 0, CH2, (CH2)2 and (CH2)3.

Pod pojmom Ar koji predstavlja karbocikličku arilnu skupinu s od 6 do 18 ugljikovih atoma se podrazumijeva derivat aromatskog cikličkog ugljikovodika kao što su fenilni, naftilni, fenantrenilni radikal ili derivat kondenziranog, bicikličkog ili tricikličkog ugljikovodika koji sadrži benzenski prsten kao što je indanil, indenil, dihidronaftil, tetrahidronaftil ili fluorenil. Spajanje je provedeno ne nivou benzenskog prstena. Fenil je bio preferiran. The term Ar, which represents a carbocyclic aryl group with from 6 to 18 carbon atoms, means a derivative of an aromatic cyclic hydrocarbon such as a phenyl, naphthyl, phenanthrenyl radical or a derivative of a condensed, bicyclic or tricyclic hydrocarbon containing a benzene ring such as indanyl, indenyl, dihydronaphthyl , tetrahydronaphthyl or fluorenyl. The coupling was carried out not at the level of the benzene ring. Phenyl was preferred.

Pod pojmom (Het), koji predstavlja zasićene ili nezasićene, aromatske ili nearomatske heterocikle s od 1 do 9 ugljikovih atoma i od 1 do 5 heteroatoma odabranih između atoma kisika, dušika i sumpora, naročito su odabrani slijedeći: Under the term (Het), which represents saturated or unsaturated, aromatic or non-aromatic heterocycles with from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, the following are particularly selected:

- heterociklički monociklički radikali, na primjer tienil, furil, piranil, pirolil, imidazolil, pirazolil, piridil, pirazinil, pirimidinil, piridazinil, tiazolil, oksazolil, furazonil, pirolinil, imidazolinil, pirazolinil, tiazolinil, triazolil, tetrazolil radikali, - heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazonyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radicals,

- kondenzirani heterociklički prstenovi, na primjer benzofuranil, benzotienil, benzimidazolil, benzotiazolil, nafto[2,3-b]-tienil, tiantrenil, izobenzofuranil, kromenil, ksantenil, fenoksatiinil, indolizinil, izoindolil, 3H-indolil, indolil, indazolil, purinil, kvinolizinil, izokvinolil, kvinolil, ftalazinil, naftiridinil, kvinoksalinil, kvinazolinil, kinolinil, pteridinil, karbazolil, beta-karbolinil, akridinil, fenazinil, fenotiazinil, fenoksazinil, indolinil, izoindolinil, imidazopiridil, imidazopirimidinil ili također kondenzirani policiklički sustavi koji se sastoje od ranije definiranih heterocikličkih monocikla kao što su na primjer furo[2,3-b]pirol ili tieno[2,3-b]-furan, - fused heterocyclic rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]-thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolyzinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also condensed polycyclic systems consisting of the previously defined heterocyclic monocycles such as for example furo[2,3-b]pyrrole or thieno[2,3-b]-furan,

- ili zasićeni heterocikli kao što su pirolidin, piperidin i morfolin. - or saturated heterocycles such as pyrrolidine, piperidine and morpholine.

Pod pojmom (Alk), koji predstavlja radikale dobivene iz zasićenih ili nezasićenih, linearnih, razgranatih ili cikličkih nearomatskih ugljikovodika, su u slučaju necikličkih ugljikovodika odabrani alkilni radikali kao što su: metil, etil, propil, izopropil, butil, izobutil, terc-butil, n-pentil, n-heksil, 2-metil-pentil, 2,3-dimetil-butil, n-heptil, 2-metilheksil, 2,2-dimetilpentil, 3,3-dimetil-pentil, 3-etilpentil, n-oktil, 2,2-dimetilheksil, 3,3-dimetilheksil, 3-metil-3-etilpentil, nonil, 2,4-dimetilheptil ili n-decil, alkenilni radikali kao što su: vinil, propenil, izopropenil, alil, 2-metilalil, butenil, ili izobutenil, ili alkinil radikali kao što su: etinil, propinil, propargil, butinil ili izobutinil, te u slučajevima cikličkih radikala, cikloalkil radikali kao što su: ciklopropil, ciklobutil, ciklopentil, cikloheksil ili adamantil. Under the term (Alk), which represents radicals obtained from saturated or unsaturated, linear, branched or cyclic non-aromatic hydrocarbons, in the case of non-cyclic hydrocarbons, alkyl radicals such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl are selected , n-pentyl, n-hexyl, 2-methyl-pentyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl, 3-ethylpentyl, n -octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl radicals such as: vinyl, propenyl, isopropenyl, allyl, 2 -methylallyl, butenyl, or isobutenyl, or alkynyl radicals such as: ethynyl, propynyl, propargyl, butynyl or isobutynyl, and in the case of cyclic radicals, cycloalkyl radicals such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

Preferirani će biti metil i etil radikali. Pod CO-Alk se preferirano misli na COCH3 i COEt, pod CO-Ar se preferirano misli na benzolil radikal, u slučaju kad je m različit od nule, (CH2)m-Ar će preferirano biti benzilna skupina. Methyl and ethyl radicals will be preferred. By CO-Alk is preferably meant COCH3 and COEt, by CO-Ar is preferably meant the benzolyl radical, in the case where m is different from zero, (CH2)m-Ar will preferably be a benzyl group.

Kada R3 i R4 zajedno s dušikovim atomom s kojim su povezani tvore heterocikl, to su osobito mono- ili biciklički heterocikli koji po volji sadrže i drugi heteroatom, odabran između kisika i dušika, a u koje spadaju slijedeći nezasićeni heterocikli: pirolil, imidazolil, indolil, piridil, pirazinil, pirimidinil, piridazinil, tiazolil, oksazolil, furazolinil, pirazolinil, tiazolinil ili konkretnije, slijedeći zasićeni heterocikli: When R3 and R4 together with the nitrogen atom to which they are connected form a heterocycle, these are particularly mono- or bicyclic heterocycles that optionally contain another heteroatom, chosen between oxygen and nitrogen, and which include the following unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazolinyl, pyrazolinyl, thiazolinyl or more specifically, the following saturated heterocycles:

[image] [image]

U slučaju kada su različite Alk, Ar, Het skupine, kao i heterocikli dobiveni od R3 i R4 vezanih na dušik, supstituirane, biti će naročito supstituirane sa slijedećim radikalima: In the case when different Alk, Ar, Het groups, as well as heterocycles obtained from R3 and R4 attached to nitrogen, are substituted, they will be especially substituted with the following radicals:

- halogen, naime fluorom, klorom, bromom ili jodom, alkoksi kao što je: metoksi, etoksi, propiloksi, izopropiloksi, butiloksi, alkiltio kao što je metiltio, etiltio, propiltio, izopropiltio, butiltio, amino, alkilamino, kao što je metilamino ili etilamino, dialkilamino kao što je dimetilamino, dietilamino, metiletilamino, pri čemu je svaki od tih dialkilamino radikala po volji u oksidiranom obliku, aminoalkil kao što je aminometil ili aminoetil, dialkilaminoalkil kao što je dimetilamino-metil ili etil, dialkilaminoalkiloksi kao što je dimetilaminoetiloksi, hidroksil po volji aciliran, acil kao što je acetil, propionil, butiril, benzoil, esterificiran karboksi kao što je alkoksi-karbonil na primjer metoksi-karbonil ili etoksi-karbonil, ciano, trifluorometil, aril kao što je fenil, aralkil kao što je benzil, alkil, alkenil ili alkinil, pri čemu su sami radikali po volji supstituirani s halogenom, alkil, alkoksi, alkiltio, amino, alkilamino ili dialkilamino radikalima naznačenim u ranijem tekstu. - halogen, namely fluorine, chlorine, bromine or iodine, alkoxy such as: methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino, such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino, methylethylamino, wherein each of these dialkylamino radicals is optionally in oxidized form, aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkyloxy such as dimethylaminoethyloxy, hydroxyl optionally acylated, acyl such as acetyl, propionyl, butyryl, benzoyl, esterified carboxy such as alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, aralkyl such as benzyl , alkyl, alkenyl or alkynyl, wherein the radicals themselves are optionally substituted with halogen, alkyl, alkoxy, alkylthio, amino, alkylamino or dialkylamino radicals indicated in the previous to the text.

Naravno, izraz "supstituiran" ukazuje na to da može biti prisutan jedan ili više identičnih ili različitih supstituenata. Na primjer, kada je alkilna skupina metil radikal supstiturian s jednim ili više halogenih atoma, to osobito mogu biti: CH2Cl, CH2F, CHF2 i CF3. Of course, the term "substituted" indicates that one or more identical or different substituents may be present. For example, when the alkyl group is a methyl radical substituent with one or more halogen atoms, these can especially be: CH2Cl, CH2F, CHF2 and CF3.

U slučaju (Het)-a, supstitucija se može odvijati na NH ili ugljikovom atomu. In the case of (Het), the substitution can take place on the NH or carbon atom.

Naravno vrijednosti R1, R2, R3 i R4, kao i n, m i m’ su neovisne jedna od druge. Of course the values of R1, R2, R3 and R4, as well as n, m and m' are independent of each other.

Izum se prirodno odnosi i na soli spojeva prikazanih formulom (I), kao što su na primjer soli dobivene djelovanjem mineralnih ili organskih kiselina na amin. To mogu biti slijedeće kiseline: kloridna, bromidna, nitratna, sulfatna, fosfatna, octena, mravlja, propionska, benzojeva, maleinska, fumarna, sukcinska, tartarna, limunska, oksalna, glioksilna, aspartatna, alkan sulfonska, kao što su metan ili etan sulfonske kiseline, arilsulfonske, kao što su benzen ili paratoluen sulfonske kiseline i arilkarboksilne. Kada spojevi prikazani formulom (I) sadrže kiselinsku skupinu izum se proširuje na soli alkalijskih metala, zemnoalkalijskih metala ili amonijaka, po volji supstituiranih. The invention naturally also relates to salts of compounds represented by formula (I), such as, for example, salts obtained by the action of mineral or organic acids on an amine. These can be the following acids: chloride, bromide, nitric, sulfate, phosphate, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulfonic, such as methane or ethane sulfonic acids, arylsulfonic, such as benzene or paratoluene sulfonic acids and arylcarboxylic. When the compounds represented by formula (I) contain an acid group, the invention extends to salts of alkali metals, alkaline earth metals or ammonia, optionally substituted.

Predmet izuma su naočito spojevi prikazani općom formulom (I), kao što je definirano ranije, kao i njihove soli, kod kojih je X atom fluora u alfa položaju, a crtkana linija ne predstavlja dvostruku vezu (prsten D zasićenog steroida). The subject of the invention is obviously the compounds represented by the general formula (I), as defined earlier, as well as their salts, where X is a fluorine atom in the alpha position, and the dashed line does not represent a double bond (ring D of a saturated steroid).

Predmet izuma su također naročito spojevi prikazani općom formulom (I), kao što je definirano u ranijem tekstu, kao i njihove soli, kod kojih je R1 atom vodika, R2 je metil radikal, Z je bilo atom vodika ili atom klora, Y predstavlja atom kisika, a crtkane linije ne predstavljaju dvostruku vezu. The subject of the invention is also particularly the compounds represented by the general formula (I), as defined in the earlier text, as well as their salts, where R1 is a hydrogen atom, R2 is a methyl radical, Z is either a hydrogen atom or a chlorine atom, Y represents an atom oxygen, and dashed lines do not represent a double bond.

Posebno naglašen predmet izuma su spojevi s općom formulom (I), kao što je definirano u ranijem tekstu, kao i njihove soli, kod kojih R3 i R4, bilo identični ili različiti, predstavljaju alkil radikal s od 1 do 6 ugljikovih atoma, ili R3 i R4 zajedno s atomom dušika na koji su vezani tvore jedan od slijedećih zasićenih heterocikla: A particularly emphasized subject of the invention are compounds with the general formula (I), as defined in the earlier text, as well as their salts, where R3 and R4, whether identical or different, represent an alkyl radical with from 1 to 6 carbon atoms, or R3 and R4 together with the nitrogen atom to which they are attached form one of the following saturated heterocycles:

[image] [image]

Posebno naglašen predmet izuma su također i spojevi prikazani općom formulom (I), kao što je definirano u ranijem tekstu, kao i njihove soli, kod kojih je X atom fluora na alfa položaju, R1 je atom vodika, R2 je metil radikal, Y je atom kisika, Z je atom vodika ili atom klora, n je jednak brojevima 2 ili 3, R3 i R4, bilo identični ili različiti, predstavljaju alkil radikal koji sadrži od 1 do 6 ugljikovih atoma, ili R3 i R4 zajedno s atomom dušika na koji su vezani tvore jedan od slijedećih zasićenih heterocikla: A particularly emphasized subject of the invention are also the compounds represented by the general formula (I), as defined in the earlier text, as well as their salts, where X is a fluorine atom in the alpha position, R1 is a hydrogen atom, R2 is a methyl radical, Y is an oxygen atom, Z is a hydrogen atom or a chlorine atom, n is equal to the numbers 2 or 3, R3 and R4, whether identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, or R3 and R4 together with a nitrogen atom to which are bonded to form one of the following saturated heterocycles:

[image] [image]

i crtkana linija ne predstavlja dvostruku vezu. and the dashed line does not represent a double bond.

Konačno predmet izuma su spojevi prikazani formulom (I) kao i njihove soli s kiselinama, imena kojih su slijedeća: Finally, the subject of the invention are the compounds shown by formula (I) as well as their salts with acids, the names of which are as follows:

- 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride

- 17-alfa-fluoro-11-beta-[4-[2-(1-dietilamino)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alfa-fluoro-11-beta-[4-[2-(1-pirolidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 4-kloro-17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-jodo-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol - 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol

- 17-alfa-fluoro-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid - 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride

- 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene

- 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(1-pirolidinil)etoksi]fenil]-estra-1,3,5(10)-trien - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene

- 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(dietilamino)etoksi]fenil]-estra-1,3,5(10)-trien - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene

- (11-beta)-17-kloro-11-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol - (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol

- 17-alfa-kloro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alpha-chloro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

- 17-alfa-jodo-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol-hidroklorid - 17-alpha-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol-hydrochloride

- 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-laktat. - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-lactate.

Predmet izuma je također postupak priprave spojeva prikazanih formulom (I), kao što je definirano ranije, u kojem je spoj prikazan formulom (II) The subject of the invention is also a process for the preparation of compounds represented by formula (I), as defined earlier, in which the compound represented by formula (II)

[image] [image]

u kojem su R2 i Z definirani ranije, RA predstavlja jednu od slijedećih skupina: wherein R 2 and Z are as defined earlier, RA represents one of the following groups:

[image] [image]

u kojim su Y, n, R3 i R4 definirani ranije, a Hal predstavlja atom halogena, je predmet djelovanja, ako je pogodno nakon zaštite i/ili aktivacije OH skupine, in which Y, n, R3 and R4 are defined earlier, and Hal represents a halogen atom, is the subject of action, if suitable after protection and/or activation of the OH group,

bilo a) redukcijskog sredstva keto skupine na položaju 17, sa svrhom postizanja spoja prikazanog formulom (IIIa): either a) a reducing agent of the keto group at position 17, with the purpose of achieving the compound shown by formula (IIIa):

[image] [image]

b) i nakon toga sredstva za halogeniranje u svrhu dobivanja spoja prikazanog formulom (I’a): b) and then halogenating agents in order to obtain the compound shown by formula (I'a):

[image] [image]

koja odgovara određenim spojevima prikazanim formulom (I), kada RA predstavlja -Ph-Y-(CH2)n-NR3R4, which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4,

ili a) hidrazina u svrhu dobivanja spoja prikazanog formulom (IIIb): or a) hydrazine in order to obtain the compound represented by formula (IIIb):

[image] [image]

b) i nakon toga od sredstva za halogeniranje u svrhu dobivanja spoja prikazanog formulom (I’b): b) and then from a halogenating agent in order to obtain the compound shown by formula (I'b):

[image] [image]

koji odgovara određenim spojevima prikazanim formulom (I), kada RA predstavlja -Ph-Y-(CH2)n-NR3R4, which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4,

spojevi prikazani formulama (II), (IIIa), (IIIb), (I’a) ili (I’b), u zaštićenom ili nezaštićenom obliku su bili podvrgnuti, ukoliko je to bilo poželjno ili nužno, jednoj ili više od slijedećih reakcija: compounds represented by formulas (II), (IIIa), (IIIb), (I'a) or (I'b), in protected or unprotected form, were subjected, if it was desirable or necessary, to one or more of the following reactions :

- uklanjanju zaštite sa zaštićene OH skupine ili skupina, - removing the protection from the protected OH group or groups,

- acilaciji/alkilaciji OH skupine ili skupina, - acylation/alkylation of the OH group or groups,

- djelovanju HNR3R4, po volji u obliku soli, kada RA predstavlja -Ph-Y-(CH2)n-Hal ili aktiviranu skupinu -Ph-Y-(CH2)n-OH. - the action of HNR3R4, optionally in salt form, when RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH.

- salifikaciji. - salification.

Redukcija 17-keto skupine u alkohol je provedena prema standardnom postupku, osobito djelovanjem alkalijskog borhidrida kao što je natrijev borhidrid u metanolu ili etanolu ili djelovanjem aluminijevog ili litijevog tetrahidrida. The reduction of the 17-keto group to an alcohol was carried out according to a standard procedure, especially by the action of an alkaline borohydride such as sodium borohydride in methanol or ethanol or by the action of aluminum or lithium tetrahydride.

Ta redukcija omogućuje preferirano dobivanje alkohola na položaju 17-beta. This reduction allows the preferred alcohol to be obtained at the 17-beta position.

Reakcija halogeniranja, koja slijedi, se preferirano provodi pomoću reagensa kao što je XSO2C4F9 u prisutnosti baze kao što je DBU (diazabicikloundekan), X je preferirano fluor. Drugi postupci halogeniranja, poznati osobama vještim u struci, mogu također biti korišteni. The halogenation reaction, which follows, is preferably carried out using a reagent such as XSO2C4F9 in the presence of a base such as DBU (diazabicycloundecane), X is preferably fluorine. Other halogenation methods known to those skilled in the art may also be used.

Kada je hidroksi skupina polaznog produkta u beta položaju, opažena je inverzija konfiguracije za vrijeme nukleofilne supstitucije i tim procesom se (reagens za halogeniranje: perfluoro-1-butan-sulfonilfluorid (FSO2C4F9)) sasvim pouzdano dobivaju spojevi prikazani formulom (I) ili (I’a) s fluorom na položaju 17-alfa. When the hydroxy group of the starting product is in the beta position, an inversion of the configuration is observed during nucleophilic substitution, and this process (halogenation reagent: perfluoro-1-butane-sulfonylfluoride (FSO2C4F9)) reliably yields the compounds shown by formula (I) or (I 'a) with fluorine at the 17-alpha position.

Djelovanje s hidrazinom se preferirano provodi u prisutnosti baze kao što je trietilamin, a halogeniranje koje slijedi se provodi pomoću X2 u bazičnom mediju, a osobito s I2. The reaction with hydrazine is preferably carried out in the presence of a base such as triethylamine, and the subsequent halogenation is carried out with X 2 in a basic medium, especially with I 2 .

Pod aktivacijom alkohola se osobito misli na uvođenje mesilata, tosilata ili triflata koji podstiću nukleofilnu supstituciju amina HNR3R4 kod spojeva prikazanih formulama (II), (IIIa), (IIIb), (I’a), (I’b) kod kojih R3 predstavlja -Ph-Y-(CH2)n-OH skupinu. The activation of alcohols means in particular the introduction of mesylate, tosylate or triflate, which promote the nucleophilic substitution of the amine HNR3R4 in the compounds shown by formulas (II), (IIIa), (IIIb), (I'a), (I'b) where R3 represents -Ph-Y-(CH2)n-OH group.

Formiranje mesilata, tosilata i triflata iz odgovarajućih alkohola se provodi u prisutnosti baze kao što je trietilamin. Zamjena alkohola s halogenim atomom, prema za to uobičajenim postupcima, može također biti prethodno razmatrana. The formation of mesylate, tosylate and triflate from the corresponding alcohols is carried out in the presence of a base such as triethylamine. Replacement of the alcohol with a halogen atom, according to the usual procedures for this, can also be previously considered.

Reakcije zaštićivanja i uklanjanja zaštite su provođene standardnim postupcima poznatim onima koji su vješti u struci. Njihov kompletan pregled je sadržan u slijedećoj publikaciji: Protective groups in organic synthesis, T.W. Greene, John Wiley & sons (1981). Protection and deprotection reactions were carried out by standard procedures known to those skilled in the art. Their complete overview is contained in the following publication: Protective groups in organic synthesis, T.W. Greene, John Wiley & sons (1981).

Zaštitna skupina P (OH → OP) može biti alkilni radikal koji sadrži 1 do 4 ugljikova atoma, benzilna skupina, tetrahidropiranilna skupina, RCRDRESi skupina u kojoj RC, RD i RE, bilo identični ili različiti, svaki neovisno jedan od drugoga predstavlja alkil radikal koji sadrži od 1 do 4 ugljikova atoma ili fenilna skupina. To su osobito Si(Me)2CMe3 ili -Si(Ph)2CMe3 ili -SiMe3 skupine. The protecting group P (OH → OP) can be an alkyl radical containing 1 to 4 carbon atoms, a benzyl group, a tetrahydropyranyl group, RCRDRESi a group in which RC, RD and RE, either identical or different, each independently represent an alkyl radical which contains from 1 to 4 carbon atoms or a phenyl group. These are especially Si(Me)2CMe3 or -Si(Ph)2CMe3 or -SiMe3 groups.

Kao primjer, reakcija uklanjanja zaštite (OP → OH na položaju 3) kada je P tetrabutildifenilsililna skupina se može provesti aktiviranjem tetrabutilamonijevog fluorida u otopini s tetrahidrofuranom. Isto je i u slučaju kad P predstavlja SO2C4F9 praćenu s reakcijom fluoridacije. As an example, the deprotection reaction (OP → OH at position 3) when P is a tetrabutyldiphenylsilyl group can be carried out by activating tetrabutylammonium fluoride in solution with tetrahydrofuran. The same is the case when P represents SO2C4F9 followed by a fluoridation reaction.

Kada je P tetrahidropiranilna skupina, uklanjanje zaštite se provodi u prisutnosti kiseline u alkoholnom otapalu, a preferirano djelovanjem kloridne kiseline u metanolu. When P is a tetrahydropyranyl group, deprotection is carried out in the presence of an acid in an alcoholic solvent, preferably by the action of hydrochloric acid in methanol.

Djelovanje spoja prikazanog formulom R3R4NH na spojeve prikazane formulama (II), (IIIa), (IIIb), (I’a), (I’b), kod kojih R2 predstavlja -Ph-Y-(CH2)n-OH ili -Ph-Y-(CH2)n-Hal skupine, je provedeno pod standardnim uvjetima za nukleofilnu supstituciju, a naročito u prisutnosti aprotičnog otapala kao što je tetrahidrofuran. Kada je OH aktiviran to su naročito: OSO2CH3, OSO2-Ph-pMe, OS2CPh3. The action of the compound represented by the formula R3R4NH on the compounds represented by the formulas (II), (IIIa), (IIIb), (I'a), (I'b), where R2 represents -Ph-Y-(CH2)n-OH or - Ph-Y-(CH2)n-Hal group, was carried out under standard conditions for nucleophilic substitution, especially in the presence of an aprotic solvent such as tetrahydrofuran. When OH is activated, these are especially: OSO2CH3, OSO2-Ph-pMe, OS2CPh3.

Reakcije alkilacije ili acilacije OH skupine na položaju 3 kao i reakcije salifikacije su provođene standardnim postupcima, poznatim osobama koje su vješte u struci. Alkylation or acylation reactions of the OH group at position 3 as well as salification reactions are carried out by standard procedures, known to persons skilled in the art.

Spojevi opće formule (I) kao i njihove soli s farmaceutski prihvatljivim kiselinama imaju naročito estrogensku, anti-estrogensku i proliferativnu aktivnost. The compounds of the general formula (I) as well as their salts with pharmaceutically acceptable acids have particularly estrogenic, anti-estrogenic and proliferative activity.

Zbog toga spojevi prikazani formulom (I) mogu biti korišteni u tretmanu poremećaja povezanih s hipofolikulinijom, na primjer odsutnost menstruacije, bolna menstruacija, ponavljani pobačaji, premenstrualni poremećaji, kod tretmana određenih o estrogenu ovisnih patologija kao što su adenoma ili rak prostate, rak dojke i njihove metastaze ili u tretmanu benignih tumora dojke, kao antiuterotrofik kao i u tretmanu zamjene kod menopauze ili perimenopauze. Therefore, the compounds represented by formula (I) can be used in the treatment of disorders associated with hypofolliculinia, for example absence of menstruation, painful menstruation, recurrent miscarriages, premenstrual disorders, in the treatment of certain estrogen-dependent pathologies such as adenoma or prostate cancer, breast cancer and their metastases or in the treatment of benign breast tumors, as an anti-uterotrophic agent as well as in the replacement treatment of menopause or perimenopause.

Pod simptomima i posljedicama povezanim s menopauzom određenije se misli na: vrućice, znojenje, vaginalnu atrofiju i suhoću, urinarne simptome, a u duljem periodu redukciju mase kostiju i povećani rizik od fraktura, te gubitak kardiovaskularne zaštite koju pružaju estrogeni. The symptoms and consequences associated with menopause more specifically mean: fever, sweating, vaginal atrophy and dryness, urinary symptoms, and in the long term, reduction of bone mass and increased risk of fractures, and loss of cardiovascular protection provided by estrogens.

Spojevi prikazani formulom (I) kao i njihove soli s farmaceutski prihvatljivim kiselinama ili bazama mogu naročito biti korištene u prevenciji ili tretmanu osteoporoze. The compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases can be particularly used in the prevention or treatment of osteoporosis.

Spojevi prikazani formulom (I) kao i njihove soli s farmaceutski prihvatljivim kiselinama ili bazama mogu također biti korištene u prevenciji ili tretmanu osteoporoze kod čovjeka. The compounds of formula (I) as well as their salts with pharmaceutically acceptable acids or bases may also be used in the prevention or treatment of osteoporosis in humans.

Oni također mogu biti korišteni za prevenciju ili tretman sekundarne osteoporoze (na primjer kortizonalne ili povezane s imobilizacijom). They can also be used to prevent or treat secondary osteoporosis (eg cortisone-related or immobilization-related).

Spojevi prikazani formulom (I) kao i njihove soli s farmaceutski prihvatljivim kiselinama ili bazama pokazuju osobito razdvojenu estrogensku aktivnost. The compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases show particularly distinct estrogenic activity.

Pod razdvojenom estrogenskom aktivnošću se misli na estrogensku aktivnost na nivou kostiju uz pokazivanje samo minimalne aktivnosti na nivou maternice, zbog čega ne dolazi do endometrijske proliferacije (puno manja aktivnost u odnosu na estradiol). By uncoupled estrogenic activity, we mean estrogenic activity at the level of the bones while showing only minimal activity at the level of the uterus, which is why endometrial proliferation does not occur (much less activity compared to estradiol).

Pored toga, spojevi iz izuma imaju slijedeće prednosti: In addition, the compounds of the invention have the following advantages:

- Oni posjeduju anti-estrogensku i/ili anti-proliferacijsku aktivnost na nivou dojke. Za razliku od estradiola, oni ne stimuliraju rast ljudskih tumorskih stanica dojke i mogu čak i inhibirati njihov rast. Zbog toga, spojevi iz izuma imaju naročitu prednost kod tretmana menopauze u žena s rizikom od raka dojke (ranije u obitelji), a koji su zbog toga isključeni iz tretmana zamjene korištenjem estradiola. - They possess anti-estrogenic and/or anti-proliferative activity at the breast level. Unlike estradiol, they do not stimulate the growth of human breast tumor cells and can even inhibit their growth. For this reason, the compounds of the invention have a particular advantage in the treatment of menopause in women at risk of breast cancer (earlier in the family), who are therefore excluded from replacement treatment using estradiol.

Oni se također mogu koristiti u tretmanu raka dojke. They can also be used in the treatment of breast cancer.

- Oni mogu dovesti do smanjenja nivoa kolesterola do razine ekvivalentne onoj pobuđenoj djelovanjem estradiola. Zbog toga, oni pojačavaju kardiovaskularnu zaštitu. - They can lead to a reduction in cholesterol levels to a level equivalent to that induced by the action of estradiol. Because of this, they enhance cardiovascular protection.

- Konačno, budući da spojevi iz izuma ne posjeduju estrogensku aktivnost na nivou maternice, oni ne zahtijevaju davanje u kombinaciji s progestomimetičkim spojem. - Finally, since the compounds of the invention do not possess estrogenic activity at the level of the uterus, they do not require administration in combination with a progestomimetic compound.

Zbog toga su predmet izuma lijekovi dobiveni iz spojeva prikazanih formulom (I) kao i njihovih soli s farmaceutski prihvatljivim kiselinama ili bazama. Therefore, the subject of the invention are drugs obtained from compounds represented by formula (I) as well as their salts with pharmaceutically acceptable acids or bases.

Konkretniji predmet izuma su spojevi prikazani formulom (I) kao i njihove soli s farmaceutski prihvatljivim kiselinama ili bazama namijenjeni prevenciji ili tretmanu osteoporoze. A more specific subject of the invention are the compounds shown by formula (I) as well as their salts with pharmaceutically acceptable acids or bases intended for the prevention or treatment of osteoporosis.

Izum se odnosi i na farmaceutske kompozicije koje sadrže najmanje jedan od ranije definiranih lijekova kao aktivni sastojak. The invention also relates to pharmaceutical compositions containing at least one of the previously defined drugs as an active ingredient.

Spojevi prikazani formulom (I) koriste se probavnim, parenteralnim ili lokalnim putem, na primjer kroz kožu. Oni mogu biti pripisani u obliku običnih ili prevučenih tableta, želatinoznih kapsula, granula, supozitorija, pesara, preparata za ubrizgavanje, masti, krema, gelova, mikrosfera, implantata, intravaginalnih prstenova, flastera, koji su priređeni prema uobičajenim postupcima. The compounds of formula (I) are used by the digestive, parenteral or local route, for example through the skin. They can be prescribed in the form of plain or coated tablets, gelatin capsules, granules, suppositories, pessaries, preparations for injection, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, which are prepared according to usual procedures.

Aktivni sastojak ili sastojci mogu biti inkorporirani s eksipijentima koji se obično koriste u tim farmaceutskim kompozicijama, kao što je talk, gumiarabika, laktoza, brašno, magnezijev stearat, kokosov maslac, vodeni ili nevodeni prijenosnici, masne tvari životinjskog ili biljnog podrijetla, parafinski derivati, glikoli, različita vlažeća, dispergirajuća ili emulzirajuća sredstva, konzervansi. The active ingredient or ingredients can be incorporated with excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, flour, magnesium stearate, coconut butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

Uobičajene doze variraju u ovisnosti o bolesti koju treba tretirati i načinu davanja; mogu na primjer kod oralnog davanja odraslim osobama varirati od 1 do 1000 mg po danu. Usual doses vary depending on the disease to be treated and the method of administration; for example, when given orally to adults, they can vary from 1 to 1000 mg per day.

Predmet izuma je također upotreba spojeva prikazanih formulom (I), kao što su ranije definirani, za pripravu lijekova koji posjeduju malu ili nikakvu aktivnost na nivou maternice, namijenjenih za tretman zamijene hormona kod menopauze ili perimenopauze, a naročito za upotrebu, karakteriziranu s time da su lijekovi namijenjeni prevenciji ili tretmanu osteoporoze. The subject of the invention is also the use of compounds represented by formula (I), as previously defined, for the preparation of drugs that have little or no activity at the level of the uterus, intended for the treatment of hormone replacement in menopause or perimenopause, and in particular for use, characterized by the fact that are drugs intended for the prevention or treatment of osteoporosis.

Spojevi prikazani formulom (II) ili (IIIa) su spojevi poznati ili lako dostupni osobi koja je vješta u struci. Konkretnije, spojevi prikazani formulom (II) kod kojih je Z=H, R2=Me i RA=-Ph-Y-(CH2)n-Hal su opisani u međunarodnoj aplikaciji WO 93/13123 (spojevi prikazani formulom II); spojevi prikazani formulom (II) kod kojih je Z=H, R2=Me i RA=-Ph-Y-(CH2)n-OH su opisani u Europskom patentu 0305242 B1 (spojevi prikazani formulom (III)), spojevi prikazani formulom (II) kod kojih je Z=H, R2=Me i RA=-Ph-Y-(CH2)n-NR3R4 su opisani u europskom patentu 0097572, certifikat Francuske adicije 2640977 ili europski patent 0305242. The compounds shown by formula (II) or (IIIa) are compounds known or readily available to a person skilled in the art. More specifically, compounds of formula (II) where Z=H, R 2 =Me and RA=-Ph-Y-(CH 2 )n-Hal are described in International Application WO 93/13123 (compounds of formula II); compounds represented by formula (II) where Z=H, R2=Me and RA=-Ph-Y-(CH2)n-OH are described in European patent 0305242 B1 (compounds represented by formula (III)), compounds represented by formula ( II) where Z=H, R2=Me and RA=-Ph-Y-(CH2)n-NR3R4 are described in European Patent 0097572, French Addition Certificate 2640977 or European Patent 0305242.

Spojevi prikazani formulom (II) u kojim Z predstavlja atom halogena su opisani u međunarodnoj aplikaciji WO 9845316, a pripravljeni su iz spoja prikazanog formulom (IV): The compounds represented by formula (II) in which Z represents a halogen atom are described in the international application WO 9845316, and are prepared from the compound represented by formula (IV):

[image] [image]

djelovanjem halogenirajućeg reagensa s ciljem dobivanja spoja prikazanog formulom (V): by the action of a halogenating reagent with the aim of obtaining the compound represented by formula (V):

[image] [image]

Spoj (V) je podvrgnut djelovanju aromatizirajućeg reagensa s prstenom A, a nakon toga djelovanju baze u svrhu dobivanja spoja prikazanog formulom (II) kod kojeg Z predstavlja atom halogena. The compound (V) is subjected to the action of an aromatizing reagent with ring A, and then to the action of a base in order to obtain the compound represented by the formula (II) where Z represents a halogen atom.

Djelovanje halogenirajućeg reagensa, kao što je N-bromosukcinimid ili N-kloromosukcinimid na spojeve prikazane formulom (IV) je konkretno provedeno u prisutnosti dipolarnog aprotičnog otapala kao što je dimetilformamid. The action of a halogenating reagent such as N-bromosuccinimide or N-chloromosuccinimide on the compounds represented by formula (IV) is specifically carried out in the presence of a dipolar aprotic solvent such as dimethylformamide.

Reakcija aromatizacije praćena reakcijom saponifikacije (djelovanje baze) je provedena prema standardnim postupcima opisanim u europskom patentu 0097572. Kao sredstvo za aromatizaciju je preferirano korištena smjesa anhidrida octene kiseline i acetil bromida, nakon čega je baza kao što je soda u metanolu korištena kao sredstvo za saponifikaciju. The aromatization reaction followed by the saponification reaction (base action) was carried out according to standard procedures described in European patent 0097572. A mixture of acetic anhydride and acetyl bromide was preferably used as an aromatization agent, after which a base such as soda in methanol was used as a saponification agent. .

Predmet izuma su također spojevi prikazani formulama (I’a), (IIIb) i (I’b) kao međuprodukti. The subject of the invention are also the compounds shown by formulas (I'a), (IIIb) and (I'b) as intermediate products.

Primjeri navedeni u daljnjem tekstu ilustriraju izum, ali ga ne ograničavaju. The following examples illustrate the invention, but do not limit it.

Otapala opisana u primjerima: AcOEt (etilni acetat), TEA (trietilamin), CH2Cl2 (diklormetan), CHCl3 (kloroform), MeOH (metanol), NH4OH (amonijev hidroksid), iPrOH (izopropilni alkohol). Solvents described in the examples: AcOEt (ethyl acetate), TEA (triethylamine), CH2Cl2 (dichloromethane), CHCl3 (chloroform), MeOH (methanol), NH4OH (ammonium hydroxide), iPrOH (isopropyl alcohol).

PRIMJER 1: 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol EXAMPLE 1: 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol

Etapa A: Redukcija Stage A: Reduction

11-beta-[4-(jodoetoksi)fenil]estra-1,3,5(10)-trien-3,17-beta-diol 11-beta-[4-(iodoethoxy)phenyl]estra-1,3,5(10)-triene-3,17-beta-diol

76 mg natrijevog borhidrida je dodano pri 0°C u otopinu 516 mg 3-hidroksi-11-beta-[4-(2-jodoetoksi)fenil]estra-1,3,5(10)-trien-17-ona pripravljenog prema postupku opisanom u WO 93/13123 u 5 ml MeOH i 5 ml THF-a, te je tijekom 5 minuta provođeno miješanje na toj temperaturi, a nakon toga tijekom 1 sata i 30 minuta pri ambijentnoj temperaturi. 20 ml 0,1 N HCl je nakon toga dodano, te je opažena kristalizacija. Dobiveno je 460 mg očekivanog produkta. 76 mg of sodium borohydride was added at 0°C to a solution of 516 mg of 3-hydroxy-11-beta-[4-(2-iodoethoxy)phenyl]estra-1,3,5(10)-trien-17-one prepared according to according to the procedure described in WO 93/13123 in 5 ml of MeOH and 5 ml of THF, and stirring was carried out for 5 minutes at that temperature, and then for 1 hour and 30 minutes at ambient temperature. 20 ml of 0.1 N HCl was then added, and crystallization was observed. 460 mg of the expected product was obtained.

Rf AcOEt /TEA 95/5 = 0,67 Rf AcOEt/TEA 95/5 = 0.67

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

7,01 i 6,61 (4H, 2d, aromatski H na položaju 11); 6,79 (1H, d, H1); 6,68 (1H, d, H4); 6,51 (1H, dd, H2); 4,11 (2H, t, CH2O); 3,94 (1H, bt, H11); 3,72 (1H, bt, H17); 3,33 (2H, t, CH2I); 0,37 (3H, s, 18-Me). 7.01 and 6.61 (4H, 2d, aromatic H at position 11); 6.79 (1H, d, H1); 6.68 (1H, d, H4); 6.51 (1H, dd, H2); 4.11 (2H, t, CH2O); 3.94 (1H, bt, H11); 3.72 (1H, bt, H17); 3.33 (2H, t, CH2I); 0.37 (3H, s, 18-Me).

Etapa B: Fluoriranje Stage B: Fluorination

17-alfa-fluoro-11-beta-[4-(2-jodoetoksi)fenil]-estra-1,3,5(10)-trien-3-ol-nonanfluorobutansulfonat. 17-alpha-fluoro-11-beta-[4-(2-iodoethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol-nonanefluorobutanesulfonate.

0,45 ml DBU-a, te nakon toga 0,20 ml perfluoro-1-butan-sulfonil-fluorida (FSO2C4F9) je pri 0°C dodano pod dušikom u suspenziju 518 mg steroida pripravljenog u etapi A u 5 ml toluena i 1 ml diklormetana, te je dobivena otopina održavana na ambijentnoj temperaturi tijekom 30 minuta. Reakcijski medij je nakon toga uliven u 20 ml vode, ekstrahiran s etilnim acetatom, ispiran, sušen i uparavan pod smanjenim tlakom, čime je dobiveno 565 mg sirovog produkta koji je pročišćavan kromatografijom na Lichrosorb RP18, uz eluiranje pomoću smjese acetonitrila i vode u omjeru 85/15. Dobiveno je 350 mg očekivanog produkta. 0.45 ml of DBU, and then 0.20 ml of perfluoro-1-butane-sulfonyl-fluoride (FSO2C4F9) were added at 0°C under nitrogen to a suspension of 518 mg of the steroid prepared in step A in 5 ml of toluene and 1 ml of dichloromethane, and the resulting solution was kept at ambient temperature for 30 minutes. The reaction medium was then poured into 20 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure, resulting in 565 mg of crude product which was purified by chromatography on Lichrosorb RP18, eluting with a mixture of acetonitrile and water in a ratio of 85 /15. 350 mg of the expected product was obtained.

Rf CH3CN/H2O 85/15 = 0,47 na LKC18F (Whatman) Rf CH3CN/H2O 85/15 = 0.47 on LKC18F (Whatman)

Točka taljenja = 110°C Melting point = 110°C

NMR (CDCl3, 250 MHz) NMR (CDCl3, 250 MHz)

7,00 (2H, m, H1 i H4); 6,93 i 6,63 (4H, 2d, AA ́BB ́, aromatski H na položaju 11); 6,82 (1H, dd, H2); 4,44 (1H, dd, J1 = 55,5 Hz J2 =5 Hz, H17); 4,14 (2H, t, CH2O); 4,03 (1H, m, H11); 3,35 (2H, t, CH2I); 0,23 (3H, d, J = 2 Hz, CH3). 7.00 (2H, m, H1 and H4); 6.93 and 6.63 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.82 (1H, dd, H2); 4.44 (1H, dd, J1 = 55.5 Hz J2 =5 Hz, H17); 4.14 (2H, t, CH2O); 4.03 (1H, m, H11); 3.35 (2H, t, CH2I); 0.23 (3H, d, J = 2 Hz, CH3).

Etapa C: Uvođenje amina praćeno s uklanjanjem zaštite. Stage C: Introduction of amine followed by deprotection.

0,4 ml piperidina je dodano u otopinu steroida pripravljenu u ranijoj etapi u 3 ml THF-a, reakcijski medij je refluksiran tijekom 2 sata nakon čega je, poslije hlađenja, uliven u 10 ml vode, ekstrahiran pomoću etilnog acetata, ispran, sušen i uparen pod sniženim tlakom, čime je dobiveno 320 mg očekivanog sirovog produkta. Nakon otapanja u 30 ml THF-a, 2 ml tetrabutilamonijevog fluorida je dodano, što je praćeno grijanjem tijekom 7 sati na temperaturi refluksiranja. Nakon što je ohlađen reakcijski medij je uliven u 20 ml vode zasićene s natrijevim bikarbonatom, ekstrahiran s etilnim acetatom, ispran, sušen i uparen pod sniženim tlakom. Dobivenih 405 mg sirovog produkta je pročišćeno kromatografijom na silika gelu uz eluiranje smjesom AcOEt i TEA u omjeru 95/5. Dobiveno je 160 mg očekivanog čistog produkta. 0.4 ml of piperidine was added to the steroid solution prepared in the earlier stage in 3 ml of THF, the reaction medium was refluxed for 2 hours after which, after cooling, it was poured into 10 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure to give 320 mg of the expected crude product. After dissolving in 30 ml of THF, 2 ml of tetrabutylammonium fluoride was added, which was followed by heating for 7 hours at reflux temperature. After cooling, the reaction medium was poured into 20 ml of water saturated with sodium bicarbonate, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure. The obtained 405 mg of crude product was purified by chromatography on silica gel eluting with a mixture of AcOEt and TEA in a ratio of 95/5. 160 mg of the expected pure product was obtained.

Rf AcOEt/TEA 95/5 0,31 na SiO2F254 Merck. Rf AcOEt/TEA 95/5 0.31 on SiO2F254 Merck.

Točka taljenja = 216°C Melting point = 216°C

NMR (CDCl3 300 MHz) NMR (CDCl3 300 MHz)

6,95 i 6,48 (4H, 2d, AA ́BB ́, aromatski H na položaju 11); 6,79 (1H, d, H1); 6,48 (1H, d, H4); 6,39 (1H, dd, H2); 4,44 (1H, dd, J = 56 Hz i 5 Hz, H17); 3,99 (1H, bt, H11); 4,26 i 3,99 (2H, 2m, CH2O), 1,65 i 1,46 (6H, m, CH2 na γ i β položaju piperidina); 1,20 do 3,20 (20H, m kostur H + CH2N i CH2 na α položaju piperidina); 0,22 (3H, d, J = 2 Hz, CH3). 6.95 and 6.48 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.79 (1H, d, H1); 6.48 (1H, d, H4); 6.39 (1H, dd, H2); 4.44 (1H, dd, J = 56 Hz and 5 Hz, H17); 3.99 (1H, bt, H11); 4.26 and 3.99 (2H, 2m, CH2O), 1.65 and 1.46 (6H, m, CH2 at γ and β position of piperidine); 1.20 to 3.20 (20H, m skeleton H + CH2N and CH2 at the α position of the piperidine); 0.22 (3H, d, J = 2 Hz, CH3).

IR (CHCl3) IR (CHCl3)

- OH 3597 cm-1 + pridružene - OH 3597 cm-1 + assocd

- aromatske 1608, 1582, 1512, 1503 cm-1 - aromatic 1608, 1582, 1512, 1503 cm-1

PRIMJER 2: 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid EXAMPLE 2: 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol hydrochloride

2 ml 4 N otopine HCl-a u etilnom acetatu je dodano u otopinu fluoriranog spoja iz primjera 1 u 10 ml etilnog acetata pri 0 do 5°C, te je došlo do kristalizacije. Dobiveno je 1,6 g bijelih kristala. 2 ml of a 4 N solution of HCl in ethyl acetate was added to a solution of the fluorinated compound from Example 1 in 10 ml of ethyl acetate at 0 to 5°C, and crystallization occurred. 1.6 g of white crystals were obtained.

Rf ACOEt/TEA 95/5 = 0,21 na SiO2F254 Merck. Rf ACOEt/TEA 95/5 = 0.21 on SiO2F254 Merck.

Točka taljenja = 216°C Melting point = 216°C

NMR (CDCl3 300 MHz) NMR (CDCl3 300 MHz)

6,95 i 6,43 (4H, 2d, AA ́BB ́, aromatski H na položaju 11); 6,79 (1H, d, H1); 6,66 (1H, d, H4); 6,59 (1H, dd, H2); 4,43 (1H, dd, J = 56 Hz i 5 Hz, H17); 3,99 (1H, bt, H11); 4,26 i 3,87 (2H, 2m, CH2O); 3,48 (pokretni 1H, NH+); 2,8 do 3,25 (2H, m, CH2N+); 0,22 (3H, d, J = 2 Hz, CH3). 6.95 and 6.43 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.79 (1H, d, H1); 6.66 (1H, d, H4); 6.59 (1H, dd, H2); 4.43 (1H, dd, J = 56 Hz and 5 Hz, H17); 3.99 (1H, bt, H11); 4.26 and 3.87 (2H, 2m, CH2O); 3.48 (mobile 1H, NH+); 2.8 to 3.25 (2H, m, CH2N+); 0.22 (3H, d, J = 2 Hz, CH3).

IR (CHCl3) IR (CHCl3)

- OH 3598 cm-1 + pridruženi - OH 3598 cm-1 + assocd

- NH+ apsorpcije - NH+ absorption

- aromatski 1610, 1582, 1512 cm-1 - aromatic 1610, 1582, 1512 cm-1

PRIMJER 3: 17-alfa-fluoro-11-beta-[4-[2-(1-dietilamino)etoksi)fenil]-estra-1,3,5(10)-trien-3-ol EXAMPLE 3: 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

Postupak je proveden kao i kod primjera 1, no uz korištenje dietilamina umjesto piperidina za vrijeme provedbe etape C, dobiven je 0,141 g očekivanog produkta. The procedure was carried out as in example 1, but with the use of diethylamine instead of piperidine during stage C, 0.141 g of the expected product was obtained.

Rf AcOEt/Et3N 99/1 = 0,15 na SiO2F254 Merck. Rf AcOEt/Et3N 99/1 = 0.15 on SiO2F254 Merck.

NMR (CDCl3 300 MHz) NMR (CDCl3 300 MHz)

0,24 (d, CH3 na položaju 18); 1,05 (t, CH3CH2N); 2,64 (q, CH3CH2N); 2,83 (t, O-CH2-CH2N); 3,95 (t, CH2O); 4,00 (bt, H11); 4,44 (dd, J = 56 Hz i 5 Hz, H17); 6,32 (d, H1), 6,38 (dd, H2); 6,53 (d, H4); 6,57 i 6,96 (AA ́BB ́, aromatski H na položaju 11); 0.24 (d, CH3 at position 18); 1.05 (t, CH3CH2N); 2.64 (q, CH 3 CH 2 N); 2.83 (t, O-CH2-CH2N); 3.95 (t, CH2O); 4.00 (bt, H11); 4.44 (dd, J = 56 Hz and 5 Hz, H17); 6.32 (d, H1), 6.38 (dd, H2); 6.53 (d, H4); 6.57 and 6.96 (AA ́BB ́, aromatic H at position 11);

PRIMJER 4: 17-alfa-fluoro-11-beta-[4-[2-(1-pirolidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ol EXAMPLE 4: 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

Postupak je proveden kao i kod primjera 1, no uz korištenje pirolidina umjesto piperidina za vrijeme provedbe etape C. Dobiveno je 0,049 g očekivanog produkta. The procedure was carried out as in example 1, but with the use of pyrrolidine instead of piperidine during step C. 0.049 g of the expected product was obtained.

Rf AcOEt/Et3N 95/5 = 0,18 na SiO2F254 Merck. Rf AcOEt/Et3N 95/5 = 0.18 on SiO2F254 Merck.

NMR (CDCl3 300 MHz) NMR (CDCl3 300 MHz)

0,28 (d, CH3 na položaju 18); 2,70 (m, piroidin); 3,03 (t, CH2N); 3,98 (t, CH2O); 4,45 (dd, H17): 6,37 (dd, H2); 6,41 (d, H4); 6,50 i 6,96 (AA ́BB ́, aromatski H na položaju 11); 6,78 (d, H1) 0.28 (d, CH3 at position 18); 2.70 (m, pyridine); 3.03 (t, CH2N); 3.98 (t, CH2O); 4.45 (dd, H17): 6.37 (dd, H2); 6.41 (d, H4); 6.50 and 6.96 (AA ́BB ́, aromatic H at position 11); 6.78 (d, H1)

PRIMJER 5: 4-kloro-17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ol EXAMPLE 5: 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5(10)-trien-3-ol

Etapa A: Zaštita 3-hidroksi-4-kloro-3-[[dimetil(2,2-dimetil)etil)silil]oksi]-11-beta-[4-[2-(1-piperidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ona. Step A: Protection of 3-hydroxy-4-chloro-3-[[dimethyl(2,2-dimethyl)ethyl)silyl]oxy]-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl] -estra-1,3,5(10)-trien-3-one.

1,3 g t-butildimetilsilil klorida je dodano u otopinu 4-kloro-3-hidroksi-11-beta-[4-[2-(1-piperidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ona pripravljenog djelovanjem NCS-a na odgovarajući Δ 4-5 9-10, 3-on derivat, što je praćeno uz reakciju aromatizacije prstena A u 30 ml CH2Cl2. Reakcijska smjesa je ohlađena do 0°C, te je nakon toga dokapavanjem dodano 1,13 ml TEA. Nakon 5 minuta pri 0°C, reakcijska smjesa je dovedena na ambijentnu temperaturu i održavana na njoj 3 sata, što je praćeno ulijevanjem u 100 ml vode. Nakon sušenja, organska faza je uparena pod sniženim tlakom čime je dobiveno 4,55 g sirovog produkta koji je pročišćen kromatografijom na silika gelu, uz eluiranje smjesom AcOEt i 1.3 g of t-butyldimethylsilyl chloride was added to a solution of 4-chloro-3-hydroxy-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-ester-1,3,5(10) -trien-3-one prepared by the action of NCS on the corresponding Δ 4-5 9-10, 3-one derivative, which was followed by the aromatization reaction of ring A in 30 ml of CH2Cl2. The reaction mixture was cooled to 0°C, after which 1.13 ml of TEA was added dropwise. After 5 minutes at 0°C, the reaction mixture was brought to ambient temperature and maintained there for 3 hours, which was followed by pouring into 100 ml of water. After drying, the organic phase was evaporated under reduced pressure to obtain 4.55 g of crude product, which was purified by chromatography on silica gel, eluting with a mixture of AcOEt and

TEA u omjeru 98/2. Dobiveno je 2,68 g očekivanog čistog produkta. TEA in the ratio 98/2. 2.68 g of the expected pure product was obtained.

Rf AcOEt/TEA 90/10 = 0,58 na SiO2F254 Merck. Rf AcOEt/TEA 90/10 = 0.58 on SiO2F254 Merck.

IR (CHCl3) IR (CHCl3)

C=O 1733 cm-1 C=O 1733 cm-1

aromatski C-H 2936 - 2859 cm-1 aromatic C-H 2936 - 2859 cm-1

Etapa B: Redukcija Stage B: Reduction

4-kloro-3-[[dimetil-(2,2-dimetiletil)silil)oksi)-11-beta-[4-[2-(1-piperidinil)etoksi)fenil]-estra-1,3,5(10)-trien-3-ol. 4-chloro-3-[[dimethyl-(2,2-dimethylethyl)silyl)oxy)-11-beta-[4-[2-(1-piperidinyl)ethoxy)phenyl]-estra-1,3,5( 10)-trien-3-ol.

189 mg NaBH4 je dodano u otopinu steroida, dobivenog u prijašnjoj etapi, u 15 ml metanola, smjesa je ohlađena pomoću ledene kupelji i miješana tijekom 5 minuta pri temperaturi od 0 do 5°C, te nakon toga još 30 minuta na ambijentnoj temperaturi. Reakcijska smjesa je ulivena u 100 ml vode, te je ekstrahirana pomoću etilnog acetata, isprana, sušena i uparena pod sniženim tlakom. Dobiveno je 1,5 g očekivanog produkta. 189 mg of NaBH4 was added to a solution of the steroid, obtained in the previous step, in 15 ml of methanol, the mixture was cooled using an ice bath and stirred for 5 minutes at a temperature of 0 to 5°C, and then for another 30 minutes at ambient temperature. The reaction mixture was poured into 100 ml of water, extracted with ethyl acetate, washed, dried and evaporated under reduced pressure. 1.5 g of the expected product was obtained.

Rf AcOEt/TEA 90/10 = 0,40 na SiO2F254 Merck. Rf AcOEt/TEA 90/10 = 0.40 on SiO2F254 Merck.

Etapa C: Fluoriranje i nakon toga uklanjanje zaštite Stage C: Fluoridation and subsequent deprotection

- Fluoriranje - Fluoridation

0,90 ml DBU-a i 0,04 ml perfluorobutan-sulfonil-fluorida je dodano pri ambijentnoj temperaturi i u atmosferi dušika u otopinu 596 mg steroida, dobivenog u prijašnjoj etapi, u 5 ml toluena i 1 ml CH2Cl2, te je reakcijska smjesa miješana tijekom 2 sata. Nakon ulijevanja u 20 ml vode, ekstrakcija je provedena pomoću diklormetana, praćena s ispiranjem, sušenjem i uparavanjem pod sniženim tlakom. Dobiveno je 1,23 g sirovog produkta koji je pročišćen kromatografijom na silika gelu, uz eluiranje smjesom AcOEt i TEA u omjeru 98/2. Izolirano je 0,6 g fluoriranog produkta zaštićenog na položaju 3. 0.90 ml of DBU and 0.04 ml of perfluorobutane-sulfonyl-fluoride were added at ambient temperature and in a nitrogen atmosphere to a solution of 596 mg of steroid, obtained in the previous step, in 5 ml of toluene and 1 ml of CH2Cl2, and the reaction mixture was mixed during 2 hours. After pouring into 20 ml of water, extraction was carried out using dichloromethane, followed by washing, drying and evaporation under reduced pressure. 1.23 g of crude product was obtained, which was purified by chromatography on silica gel, eluting with a mixture of AcOEt and TEA in a ratio of 98/2. 0.6 g of the fluorinated product protected at position 3 was isolated.

- Uklanjanje zaštite - Removal of protection

2 ml Bu4NF-a je dodano u otopinu fluoriranog produkta u 3 ml THF-a, te je smjesa grijana na temperaturi refluksa tijekom 4 sata, nakon čega je ohlađena i ulivena u 20 ml vode. Nakon ekstrakcije pomoću diklormetana, ispiranja i sušenja, uparavanje je provedeno pod smanjenim tlakom, sve dok nije dobiven suhi ekstrakt koji je pročišćen kromatografijom na Lichrosorb RP18, uz eluiranje smjesom MeOH/H2O/TEA u omjeru 90/9/1. Dobiveno je 65 mg očekivanog produkta. 2 ml of Bu4NF was added to a solution of the fluorinated product in 3 ml of THF, and the mixture was heated at reflux temperature for 4 hours, after which it was cooled and poured into 20 ml of water. After extraction with dichloromethane, washing and drying, evaporation was carried out under reduced pressure, until a dry extract was obtained, which was purified by chromatography on Lichrosorb RP18, eluting with a mixture of MeOH/H2O/TEA in the ratio 90/9/1. 65 mg of the expected product was obtained.

Rf MeOH H2O/TEA 90/9/1 = 0,23 na LKC18F (Whatman) Rf MeOH H2O/TEA 90/9/1 = 0.23 on LKC18F (Whatman)

NMR (CDCl3 300 MHz) NMR (CDCl3 300 MHz)

6,91 i 6,61 (4H, 2d, AA ́BB ́, aromatski H na položaju 11); 6,80 (1H, d, H1); 6,61 (1H, d, H2); 4,34 (1H, dd, J = 5 Hz i 55,5 Hz, H17); 3,98 (1H, maskirani, H11); 3,98 (2H, t, CH2O); 2,70 (2H, t, CH2N); 2,47 (4H, m, 2CH2 na α položaju dušika u piperidinu); 1,58 (4H, m, 2CH2 na β položaju dušika u piperidinu); 1,44 (2H, m, 1CH2 na γ položaju dušika u piperidinu); 0,22 (3H, d, J = 2,5 Hz, 18-Me). 6.91 and 6.61 (4H, 2d, AA ́BB ́, aromatic H at position 11); 6.80 (1H, d, H1); 6.61 (1H, d, H2); 4.34 (1H, dd, J = 5 Hz and 55.5 Hz, H17); 3.98 (1H, masked, H11); 3.98 (2H, t, CH2O); 2.70 (2H, t, CH2N); 2.47 (4H, m, 2CH2 at the α position of the piperidine nitrogen); 1.58 (4H, m, 2CH2 at the β position of the piperidine nitrogen); 1.44 (2H, m, 1CH2 at the γ position of the piperidine nitrogen); 0.22 (3H, d, J = 2.5 Hz, 18-Me).

IR (CHCl3) IR (CHCl3)

OH 3537 cm-1 OH 3537 cm-1

Aromatski 1608, 1581, 1512 cm-1 Aromatic 1608, 1581, 1512 cm-1

Za upotrebu kao i u prijašnjim primjerima, pripravljeni su slijedeći produkti: For use as in the previous examples, the following products are prepared:

PRIMJER 6: 17-jodo-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol. EXAMPLE 6: 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol.

Rf: 0,33 (AcOEt-TEA 90-10). Rf: 0.33 (AcOEt-TEA 90-10).

IR (CHCl3) IR (CHCl3)

OH: 3600 cm-1; aromatski: 1609, 1580, 1512 cm-1. OH: 3600 cm-1; aromatic: 1609, 1580, 1512 cm-1.

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,46: (s, CH3 na položaju 18); 3,95: (m, CH2O i H11); 6,11: (H16); 6,36: (dd, H2); 6,44: (d, H4); 6,71: (d, H1); ≈6,50 do ≈6,94: (aromatski na položaju 11). 0.46: (s, CH3 at position 18); 3.95: (m, CH2O and H11); 6.11: (H16); 6.36: (dd, H2); 6.44: (d, H4); 6.71: (d, H1); ≈6.50 to ≈6.94: (aromatic at position 11).

PRIMJER 7: 17-alfa-fluoro-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol. EXAMPLE 7: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol.

Rf: 0,22 (AcOEt-TEA 99-1). Rf: 0.22 (AcOEt-TEA 99-1).

IR (CHCl3) IR (CHCl3)

OH: 3599 cm-1; aromatski: 1610, 1581, 1512 (F) cm-1 OH: 3599 cm-1; aromatic: 1610, 1581, 1512 (F) cm-1

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,26: (s, CH3 na položaju 18); 0,90: (d, CH3 na položaju 4 pipiridinila); ≈3,97: (m, CH2O i H11); 4,43: (dd, H17); 6,38: (dd, H2); 6,46: (d, H4); 6,80: (d, H1); ≈6,50 do ≈6,95: (aromatski na položaju 11). 0.26: (s, CH3 at position 18); 0.90: (d, CH3 at position 4 of piperidinyl); ≈3.97: (m, CH2O and H11); 4.43: (dd, H17); 6.38: (dd, H2); 6.46: (d, H4); 6.80: (d, H1); ≈6.50 to ≈6.95: (aromatic at position 11).

PRIMJER 8: 17-alfa-fluoro-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid. EXAMPLE 8: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol- hydrochloride.

Točka taljenja = 200°C Melting point = 200°C

Rf: 0,15 (AcOEt-TEA 99-1). Rf: 0.15 (AcOEt-TEA 99-1).

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,16: (s, CH3 na položaju 18); 0,90: (d, CH3 na položaju 4 pipiridinila); 3,98: (bs, H11); 4,25: (bs, CH2O); 4,45: (dd, H17); 6,31: (dd, H2); 6,48: (d, J=2 H4); 6,71: (d, H1); 6,71 do 7,02: (aromatski na položaju 11); 8,97 (s, OH na položaju 3). 0.16: (s, CH3 at position 18); 0.90: (d, CH3 at position 4 of piperidinyl); 3.98: (bs, H11); 4.25: (bs, CH2O); 4.45: (dd, H17); 6.31: (dd, H2); 6.48: (d, J=2 H4); 6.71: (d, H1); 6.71 to 7.02: (aromatic at position 11); 8.97 (s, OH at position 3).

PRIMJER 9: 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien. EXAMPLE 9: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene.

Rf: 0,23 (MeOH-H2O-TEA 94-5-1). Rf: 0.23 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3) IR (CHCl3)

odsutnost OH; aromatski: 1610, 1578, 1512, 1501 cm-1 absence of OH; aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,22: (s, CH3 na položaju 18); 1,58: (m) i 2,47 (m): piperidin; 2,70: (t, CH2-N): 3,73: (s, CH3-O); 3,98: (t, CH2O); 4,43: (dd, H17); 6,50: (dd, H2); 6,64: (bs, H4); 6,88: (d, H1); ≈6,62 do ≈6,97: (aromatski na položaju 11). 0.22: (s, CH3 at position 18); 1.58: (m) and 2.47 (m): piperidine; 2.70: (t, CH2-N): 3.73: (s, CH3-O); 3.98: (t, CH 2 O); 4.43: (dd, H17); 6.50: (dd, H2); 6.64: (bs, H4); 6.88: (d, H1); ≈6.62 to ≈6.97: (aromatic at position 11).

PRIMJER 10: 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien. EXAMPLE 10: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene.

Točka taljenja = 132°C. Melting point = 132°C.

Rf: 0,21 (MeOH-H2O-TEA 94-5-1). Rf: 0.21 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3) IR (CHCl3)

aromatski: 1610, 1578, 1512, 1501 cm-1 aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,22: (s, CH3 na položaju 18); 1,78: (m) i 2,58 (m): pirolidin; 2,83: (t, CH2-N): 3,73: (s, CH3-O); 3,99: (t, CH2O); 4,43: (dd, H17); 6,50: (dd, H2); ≈6,65: (H4); 6,89: (d, H1); ≈6,62 do ≈6,97: (aromatski na položaju 11). 0.22: (s, CH3 at position 18); 1.78: (m) and 2.58 (m): pyrrolidine; 2.83: (t, CH2-N): 3.73: (s, CH3-O); 3.99: (t, CH2O); 4.43: (dd, H17); 6.50: (dd, H2); ≈6.65: (H4); 6.89: (d, H1); ≈6.62 to ≈6.97: (aromatic at position 11).

PRIMJER 11: 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(dietilamino)-etoksi]-fenil]-estra-1,3,5(10)-trien. EXAMPLE 11: 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)-ethoxy]-phenyl]-estra-1,3,5(10)-triene.

Rf: 0,20 (MeOH-H2O-TEA 94-5-1). Rf: 0.20 (MeOH-H2O-TEA 94-5-1).

IR (CHCl3) IR (CHCl3)

aromatski: 1610, 1578, 1512, 1501 cm-1 aromatic: 1610, 1578, 1512, 1501 cm-1

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,22: (s, CH3 na položaju 18); 1,04: (t) i 2,61 (q): N-Et2; 2,82: (t, CH2-N): 3,73: (s, CH3-O); 3,94: (t, CH2O); 4,43: (dd, H17); 6,49: (dd, H2); 6,64: (d, H4); 6,88: (d, H1); ≈6,62 do ≈6,96: (aromatski na položaju 11). 0.22: (s, CH3 at position 18); 1.04: (t) and 2.61 (q): N-Et2; 2.82: (t, CH2-N): 3.73: (s, CH3-O); 3.94: (t, CH 2 O); 4.43: (dd, H17); 6.49: (dd, H2); 6.64: (d, H4); 6.88: (d, H1); ≈6.62 to ≈6.96: (aromatic at position 11).

m kostur H + CH2N i CH2 na α položaju piperidina); 0,22 (3H, d, J = 2 Hz, CH3). m skeleton H + CH2N and CH2 at the α position of piperidine); 0.22 (3H, d, J = 2 Hz, CH3).

PRIMJER 12: (11-beta)-17-kloro-11-[4-[2-(1-piperidinil)-etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol. EXAMPLE 12: (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol .

Rf: 0,25 (CH2Cl2-MeOH-NH4OH 95-5-0,5). Rf: 0.25 (CH2Cl2-MeOH-NH4OH 95-5-0.5).

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,60: (s, CH3 na položaju 18); ≈4,01: (m, CH2O i H11): 5,60: (bd, H16); 6,38: (dd, H2); 6,45: (d, H4); 6,70: (d, H1); ≈6,50 do ≈6,93: (aromatski na položaju 11). 0.60: (s, CH3 at position 18); ≈4.01: (m, CH2O and H11): 5.60: (bd, H16); 6.38: (dd, H2); 6.45: (d, H4); 6.70: (d, H1); ≈6.50 to ≈6.93: (aromatic at position 11).

PRIMJER 13: 17-kloro-11-beta-[4-[2-(1-piperidinil)-etoksi]-fenil]-estra-1,3,5(10)-trien-3-ol. EXAMPLE 13: 17-chloro-11-beta-[4-[2-(1-piperidinyl)-ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol.

Rf: 0,10 (CH2Cl2-MeOH-NH4OH 94-5-0,5). Rf: 0.10 (CH2Cl2-MeOH-NH4OH 94-5-0.5).

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,41: (s, CH3 na položaju 18); ≈3,98: (m, CH2O i H11 i H17): 6,39: (dd, H2); 6,48: (H4); 6,79: (d, H1); ≈6,48 do ≈6,94: (aromatski na položaju 11). 0.41: (s, CH3 at position 18); ≈3.98: (m, CH2O and H11 and H17): 6.39: (dd, H2); 6.48: (H4); 6.79: (d, H1); ≈6.48 to ≈6.94: (aromatic at position 11).

PRIMJER 14: 17-jodo-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol-hidroklorid. EXAMPLE 14: 17-iodo-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol- hydrochloride.

Točka taljenja = 260°C. Melting point = 260°C.

Rf: 0,33 (AcOEt-TEA 90-10). Rf: 0.33 (AcOEt-TEA 90-10).

NMR (DMSO, 300 MHz) NMR (DMSO, 300 MHz)

0,29: (s, CH3 na položaju 18); 4,02: (bt, H11); 4,25: (bs, CH2O): 6,15: (bs, H16); 6,29: (dd, H2); 6,48: (d, H4); 6,64: (d, H1); ≈6,73 do ≈7,01: (aromatski na položaju 11); 8,94 do ≈9,78: mobilni H. 0.29: (s, CH3 at position 18); 4.02: (bt, H11); 4.25: (bs, CH 2 O): 6.15: (bs, H 16 ); 6.29: (dd, H2); 6.48: (d, H4); 6.64: (d, H1); ≈6.73 to ≈7.01: (aromatic at position 11); 8.94 to ≈9.78: mobile H.

PRIMJER 15: 17-alfa-fluoro-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-laktat. EXAMPLE 15: 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol- lactate.

Točka taljenja = 138°C. Melting point = 138°C.

Rf: 0,22 (AcOEt-TEA 99-1). Rf: 0.22 (AcOEt-TEA 99-1).

NMR (CDCl3, 300 MHz) NMR (CDCl3, 300 MHz)

0,22: (d, CH3 na položaju 18); ≈3,15: (CH2N); ≈3,94: (m, CH2-O); ≈3,98: (m, H11); 4,43: (dd, H17); 6,42: (dd, H2); 6,78: (d, H1); ≈6,48 do ≈6,97: (aromatski na položaju 11); 1,36 (d) i 4,09 (m): laktat. 0.22: (d, CH3 at position 18); ≈3.15: (CH2N); ≈3.94: (m, CH2-O); ≈3.98: (m, H11); 4.43: (dd, H17); 6.42: (dd, H2); 6.78: (d, H1); ≈6.48 to ≈6.97: (aromatic at position 11); 1.36 (d) and 4.09 (m): lactate.

Farmakološki testovi Pharmacological tests

Efekt na proliferaciju stanica grudi Effect on breast cell proliferation

Proliferativna aktivnost molekula je studirana u odnosu na aktivnost estradiola u kulturi ljudskih MCF-7 stanica grudi. The proliferative activity of the molecule was studied in relation to the activity of estradiol in cultured human MCF-7 breast cells.

Da bi se pokazao efekt pobude kod estradiola i/ili kod testiranih molekula, medij održavane stanične kulture (bogat u faktoru rasta i steroidima) je zamijenjen s osiromašenim medijem, koji između ostalog ne sadrži steroide (DMEM s 5% serumom bez steroida i bez fenol crvenila). Stanice su tijekom 2 dana bile podvrgnute tom tretmanu prije početka testa. Nakon što je studirani produkt bio 7 dana prisutan u kulturi, stanična proliferacija je procijenjena iz određivanja DNA. Kod svakog testa, efekt estradiola kod 10-10 M (stanični rast u prisutnosti estradiola umanjen za stanični rast u prisutnosti otapala) određuje 100%-tnu aktivnost pobude. Aktivnost molekula je procijenjena iz usporedbe s tom unutarnjom kontrolom. Molekule koje su pobuđivale identičan rast stanica kao i onaj opažen kod samog otapala su klasificirane kao “neaktivne”, one koje su pobuđivale manji rast stanica u odnosu na rast opažen kod otapala su klasificirane kao “inhibitori”. In order to show the stimulation effect of estradiol and/or the tested molecules, the medium of the maintained cell culture (rich in growth factor and steroids) was replaced with a depleted medium, which, among other things, does not contain steroids (DMEM with 5% serum without steroids and without phenol redness). The cells were subjected to this treatment for 2 days before the start of the test. After the studied product was present in the culture for 7 days, cell proliferation was assessed from DNA determination. In each assay, the effect of estradiol at 10-10 M (cell growth in the presence of estradiol minus cell growth in the presence of solvent) determines 100% stimulatory activity. The activity of the molecules was estimated from comparison with this internal control. Molecules that stimulated cell growth identical to that observed in the solvent alone were classified as "inactive", those that stimulated less cell growth compared to the growth observed in the solvent were classified as "inhibitors".

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Studija utjecaja produkta na kosti ovariektomizirane ženke štakora u dobi od 3 mjeseci Study of the effect of the product on the bones of ovariectomized female rats at the age of 3 months

Spojevi su testirani u svrhu određivanja njihovog efekta na masu kostiju, te na formiranje i resorpcijsku aktivnost u modelu ovariektomiziranog štakora u dobi od 3 mjeseca. Životinje su tretirane na preventivan način. The compounds were tested in order to determine their effect on bone mass, and on the formation and resorption activity in the ovariectomized rat model at the age of 3 months. The animals were treated in a preventive manner.

Životinje: Animals:

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Produkti: Products:

1 - Produkt za testiranje: produkt iz primjera 1. 1 - Test product: product from example 1.

* prijenosnik (prijenosnici): kukuruzno ulje, 0,5% metilceluloze * carrier(s): corn oil, 0.5% methylcellulose

* broj davanja: jednom/dan; 5 dana/tjedan za 4 tjedna * number of administrations: once/day; 5 days/week for 4 weeks

* način davanja: oralni način za produkt * method of administration: oral method for the product

* volumeni: 5 ml/kg (p.o.) * volumes: 5 ml/kg (p.o.)

* period između zadnjeg ubrizgavanja i žrtvovanja: 24 sata * period between last injection and sacrifice: 24 hours

* broj davanja: 20 * number of benefits: 20

2 - Preporučeni produkt: 17β-estradiol je davan potkožnim putem u dozi od 0,1 ili 0,01 mg/kg/d u otopini smjese kukuruznog ulja i benzilnog alkohola (99:1, v/v) s volumenom od 0,2 ml/kg. 2 - Recommended product: 17β-estradiol was administered subcutaneously in a dose of 0.1 or 0.01 mg/kg/d in a solution of a mixture of corn oil and benzyl alcohol (99:1, v/v) with a volume of 0.2 ml / kg.

Eksperimentalni protokol Experimental protocol

Životinje Animals

Studija je provedena s ovariektomiziranim ženkama štakora u dobi od 3 mjeseca. Životinje su držane u klimatiziranoj prostoriji (temperatura 20°C ± 2°C) i razvrstane u kaveze u grupama od po 4. Životinje su primile libitum, demineraliziranu vodu i komprimiranu hranu (tablete: AO4CR-10 UAR). The study was conducted with ovariectomized female rats at the age of 3 months. The animals were kept in an air-conditioned room (temperature 20°C ± 2°C) and sorted into cages in groups of 4. The animals received ad libitum, demineralized water and compressed food (tablets: AO4CR-10 UAR).

Kirurgija Surgery

Tri mjeseca stare ženke štakora približne težine od 250 g su ovariektomizirane pod anestezijom pomoću Imalgene 1000 davanog intraperitonealnim putem (i.p.) u dozi od 100 mg/kg i ispod volumena od 1 ml/kg. One su također primile i Nembutal (3 mg/kg i.p. ispod volumena od 0,3 ml/kg). Three-month-old female rats weighing approximately 250 g were ovariectomized under anesthesia with Imalgene 1000 administered intraperitoneally (i.p.) at a dose of 100 mg/kg and under a volume of 1 ml/kg. They also received Nembutal (3 mg/kg i.p. under a volume of 0.3 ml/kg).

Nakon lateralnog zarezivanja, razdvojeni su koža i mišići. Uklanjanje jajnika je provedeno nakon podvezivanja jajovoda. After the lateral incision, the skin and muscles are separated. Removal of the ovaries was performed after ligation of the fallopian tubes.

"SHAM" kontrolni štakori su anestetizirani pod istim uvjetima. Nakon zarezivanja kože i mišića svaki jajnik je iznjet i nakon toga zamjenjen in situ. "SHAM" control rats were anesthetized under the same conditions. After incising the skin and muscles, each ovary was removed and then replaced in situ.

Tretman Treatment

Djelovanja produkata su određena preventivnim tretmanom. Oni su davani odmah nakon ovariektomije. Životinje su raspoređene u skupine od po 8. The effects of the products are determined by preventive treatment. They were administered immediately after ovariectomy. The animals are arranged in groups of 8.

Skupina 1: "SHAM" kontrolni štakori su primili prijenosnik ili prijenosnike. Group 1: "SHAM" control rats received vehicle or vehicles.

Skupina 2 "OVX" kontrolni štakori su primili prijenosnik ili prijenosnike. Group 2 "OVX" control rats received vehicle or vehicles.

Skupine X: "OVX" štakori su primili pojedinačno definirane doze produkta ili produkata koji se testiraju. Groups X: "OVX" rats received individually defined doses of the product or products being tested.

Uzorci krvi Blood samples

Nakon 4 tjedna (trajanje studije), životinjama je odrubljena glava pomoću giljotine. Serumi prikupljeni nakon centrifugiranja su čuvani na -20°C. After 4 weeks (the duration of the study), the animals were decapitated using a guillotine. Sera collected after centrifugation were stored at -20°C.

Ravnoteža lipida u serumima će biti uspostavljena iz određivanja ukupne količine kolesterola, triglicerida i fosfolipida u alikvotu od 500 �l seruma. Smanjenje nivoa kolesterola u serumima je izraženo u relativnom % u odnosu na nivo dobiven kod ovariektomiziranih životinja koje su primile samo otapalo. The balance of lipids in serums will be established from the determination of the total amount of cholesterol, triglycerides and phospholipids in an aliquot of 500 l of serum. The decrease in serum cholesterol level is expressed in relative % compared to the level obtained in ovariectomized animals that received only solvent.

Uzorci organa Organ samples

Nakon žrtvovanja životinja, slijedeći organi su uklonjeni: After sacrificing the animals, the following organs were removed:

- genitalni trakt - genital tract

Uklonjene su maternice. Izvagane su. Porast težine je izražen u % težine uterusa ovariektomiziranih životinja koje su primile samo otapalo. The uteruses were removed. They are weighed. The increase in weight is expressed in % of the weight of the uterus of ovariectomized animals that received only solvent.

- na nivou kostiju: - at the bone level:

Masa kostiju (BMD ili mineralna gustoća kostiju) je mjerena pomoću dvofotonska dualno energijska apsorpciometrija rendgenskih (DEXA). Mjerenja su vršena na odrezanim kostima očišćenim od svega mekog tkiva. BMD (mineralna gustoća kostiju) je mjerena na cijeloj kosti kao i na metafisealnom dijelu na nivou proksimalnog kraja lijeve tibije. Ta zona je definirana kao područje najbogatije u trabekularnim kostima; i kao posljedica toga, je najosjetljivija na variranja volumena kostiju i mineralne gustoće kostiju. Bone mass (BMD or bone mineral density) was measured using two-photon dual-energy X-ray absorptiometry (DEXA). Measurements were made on cut bones cleaned of all soft tissue. BMD (bone mineral density) was measured on the whole bone as well as on the metaphyseal part at the level of the proximal end of the left tibia. This zone is defined as the area richest in trabecular bones; and as a result, is most sensitive to variations in bone volume and bone mineral density.

Rezultat je izražen u % prema slijedećoj formuli: The result is expressed in % according to the following formula:

Testirani produkt BMD -OVX BMD × 100 Tested product BMD -OVX BMD × 100

SHAM BMD - OVX BMD SHAM BMD - OVX BMD

[image] [image]

Claims (17)

1. Spojevi prikazani općom formulom (I): [image] naznačeni time, da: R1 predstavlja vodikov atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk ili (CO)-Alk radikal, R2 predstavlja radikal dobiven od ravnog ili razgranatog, zasićenog ili nezasićenog ugljikovodika koji sadrži 1 do 6 ugljikovih atoma X predstavlja atom halogena, Y predstavlja jednostruku vezu, O, NH, S, SO, ili SO2, Z predstavlja vodikov atom ili halogeni atom, n je jednak brojevima 2, 3, 4 ili 5, ili R3 i R4, identični ili različiti, predstavljaju vodikov atom, (CH2)m’-Ar, (CH2)m’-Het ili (CH2)m’-Alk skupinu, ili R3 i R4 tvore zajedno s dušikovim atomom, s kojim su povezani, aromatski ili nearomatski, zasićeni ili nezasićeni mono- ili policiklički heterocikl s 3 do 15 članova koji po volji sadrže 1 do 3 dodatna hetero atoma izabrana između kisika, sumpora i dušika, nesupstituirani ili supstituirani, Ar predstavlja karbocikličku arilnu skupinu koja sadrži 6 do 18 ugljikovih atoma, Het predstavlja zasićeni ili nezasićeni aromatski ili nearomatski heterocikl koji sadrži od 1 do 9 ugljikovih atoma i od 1 do 5 heteroatoma odabranih između atoma kisika, dušika ili sumpor, Alk predstavlja radikal dobiven iz zasićenog ili nezasićenog, linearnog, razgranatog ili cikličkog, nearomatskog ugljikovodika i sadrži od 1 do 12 uglikovih atoma, radikali Ar, Het ili Alk mogu biti supstituirani ili nesupstituirani, m i m’ predstavljaju brojeve 0, 1, 2 ili 3, crtkane linije predstavljaju moguću dvostruku vezu, kao i njihove soli s dodanim bazama ili kiselinama.1. Compounds represented by the general formula (I): [image] indicated that: R1 represents a hydrogen atom, (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk or (CO)-Alk radical, R2 represents a radical obtained from a straight or branched, saturated or unsaturated hydrocarbon containing 1 to 6 carbon atoms X represents a halogen atom, Y represents a single bond, O, NH, S, SO, or SO2, Z represents a hydrogen atom or a halogen atom, n is equal to the numbers 2, 3, 4 or 5, or R3 and R4, identical or different, represent a hydrogen atom, (CH2)m'-Ar, (CH2)m'-Het or (CH2)m'-Alk group, or R3 and R4 form together with a nitrogen atom, with which are linked, aromatic or non-aromatic, saturated or unsaturated mono- or polycyclic heterocycle with 3 to 15 members optionally containing 1 to 3 additional hetero atoms selected from oxygen, sulfur and nitrogen, unsubstituted or substituted, Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, Het represents a saturated or unsaturated aromatic or non-aromatic heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, Alk represents a radical obtained from saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon and contains from 1 to 12 carbon atoms, radicals Ar, Het or Alk can be substituted or unsubstituted, m and m' represent the numbers 0, 1, 2 or 3, dashed lines represent a possible double bond, as well as their salts with added bases or acids. 2. Spojevi prikazani općom formulom (I) kao što je definirano u zahtjevu 1, kao i njihove soli, naznačeni time, da je X atom fluora na alfa položaju, a crtkana linija ne predstavlja dvostruku vezu.2. Compounds shown by the general formula (I) as defined in claim 1, as well as their salts, indicated that X is a fluorine atom in the alpha position, and the dashed line does not represent a double bond. 3. Spojevi prikazani općom formulom (I) kao što je definirano u zahtjevu 1 ili 2, kao i njihove soli, naznačeni time, da R1 predstavlja atom vodika, R2 je metil radikal, a Z je atom vodika ili atom klora, Y predstavlja atom kisika, a crtkana linija ne predstavlja dvostruku vezu.3. Compounds represented by the general formula (I) as defined in claim 1 or 2, as well as their salts, characterized in that R1 represents a hydrogen atom, R2 is a methyl radical, and Z is a hydrogen atom or a chlorine atom, Y represents an atom oxygen, and the dashed line does not represent a double bond. 4. Spojevi prikazani općom formulom (I) kao što je definirano u bilo kojem od zahtjeva 1 do 3, kao i njihove soli, naznačeni time da: ili R3 i R4, identični ili različiti, predstavljaju alkilni radikal s 1 do 6 atoma ugljika, vodikov atom, ili R3 i R4 tvore zajedno s dušikovim atomom, na koji su vezani, jedan od slijedećih zasićenih heterocikla: [image] 4. Compounds represented by the general formula (I) as defined in any of claims 1 to 3, as well as their salts, characterized in that: or R3 and R4, identical or different, represent an alkyl radical with 1 to 6 carbon atoms, a hydrogen atom, or R3 and R4 together with the nitrogen atom, to which they are attached, form one of the following saturated heterocycles: [image] 5. Spojevi prikazani općom formulom (I) kao što je definirano u bilo kojem od zahtjeva 1 do 4, kao i njihove soli, naznačeni time, da je X atom fluora na alfa položaju, R1 je atom vodika, R2 je metil radikal, Y je atom kisika, Z je atom vodika ili atom klora, n je jednak brojevima 2 ili 3, ili R3 i R4, bilo identični ili različiti, predstavljaju alkil radikal koji sadrži od 1 do 6 ugljikovih atoma, ili R3 i R4 zajedno s atomom dušika na koji su vezani tvore jedan od slijedećih zasićenih heterocikla: [image] i crtkana linija ne predstavlja dvostruku vezu.5. Compounds represented by the general formula (I) as defined in any of claims 1 to 4, as well as salts thereof, characterized in that X is a fluorine atom in the alpha position, R1 is a hydrogen atom, R2 is a methyl radical, Y is an oxygen atom, Z is a hydrogen atom or a chlorine atom, n is equal to the numbers 2 or 3, or R3 and R4, whether identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, or R3 and R4 together with the nitrogen atom to which they are attached form one of the following saturated heterocycles: [image] and the dashed line does not represent a double bond. 6. Spojevi prema bilo kojem od zahtjeva 1 do 5, naznačeni time, da su: - 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid - 17-alfa-fluoro-11-beta-[4-[2-(1-dietilamino)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-alfa-fluoro-11-beta-[4-[2-(1-pirolidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 4-kloro-17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-jodo-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol - 17-alfa-fluoro-11-beta-[4-[2-(4-metil-1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol-hidroklorid - 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien - 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(1-pirolidinil)etoksi]fenil]-estra-1,3,5(10)-trien - 17-alfa-fluoro-3-metoksi-11-beta-[4-[2-(dietilamino)etoksi]fenil]-estra-1,3,5(10)-trien - (11-beta)-17-kloro-11-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol - 17-alfa-kloro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol - 17-jodo-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10),16-tetraen-3-ol-hidroklorid - 17-alfa-fluoro-11-beta-[4-[2-(1-piperidinil)etoksi]fenil]-estra-1,3,5(10)-trien-3-ol.6. Compounds according to any of claims 1 to 5, characterized in that: - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride - 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol - 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol-hydrochloride - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene - 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene - (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol - 17-alpha-chloro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol - 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol-hydrochloride - 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol. 7. Postupak priprave spojeva prikazanih formulom (I), kao što je definirano u zahtjevu 1, naznačen time da je spoj prikazan formulom (II) [image] u kojem su R2 i Z definirani ranije, RA predstavlja jednu od slijedećih skupina: [image] u kojim su Y, n, R3 i R4 definirani ranije, a Hal predstavlja atom halogena, podvrgnut djelovanju, ako je pogodno nakon zaštite i/ili aktivacije OH skupine, bilo a) redukcijskog sredstva keto skupine na položaju 17 u svrhu postizanja spoja prikazanog formulom (IIIa): [image] b) i nakon toga sredstva za halogeniranje u svrhu dobivanja spoja prikazanog formulom (I’a): [image] koji odgovara određenim spojevima prikazanim formulom (I), kada RA predstavlja -Ph-Y-(CH2)n-NR3R4, ili a) hidrazina u svrhu dobivanja spoja prikazanog formulom (IIIb): [image] b) i nakon toga sredstva za halogeniranje u svrhu dobivanja spoja prikazanog formulom (I’b): [image] koji odgovara određenim spojevima prikazanim formulom (I), kada RA predstavlja -Ph-Y-(CH2)n-NR3R4, spojevi prikazani formulama (II), (IIIa), (IIIb), (I’a) ili (I’b), u zaštićenom ili nezaštićenom obliku, su bili podvrgnuti, ukoliko je to bilo poželjno ili nužno, jednoj ili više od slijedećih reakcija: - uklanjanju zaštite sa zaštićene OH skupine ili skupina, - acilaciji/alkilaciji OH skupine ili skupina, - djelovanju HNR3R4, po volji u obliku soli, kada RA predstavlja -Ph-Y-(CH2)n-Hal ili aktiviranu skupinu -Ph-Y-(CH2)n-OH. - salifikaciji.7. Process for the preparation of compounds represented by formula (I), as defined in claim 1, characterized in that the compound is represented by formula (II) [image] wherein R 2 and Z are as defined earlier, RA represents one of the following groups: [image] in which Y, n, R3 and R4 are as defined earlier, and Hal represents a halogen atom, subjected to action, if appropriate after protection and/or activation of the OH group, either a) reducing agent of the keto group at position 17 in order to achieve the compound shown by formula (IIIa): [image] b) and then halogenating agents in order to obtain the compound shown by formula (I'a): [image] which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, or a) hydrazine in order to obtain the compound represented by formula (IIIb): [image] b) and then halogenating agents in order to obtain the compound shown by formula (I'b): [image] which corresponds to certain compounds shown by formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, compounds represented by formulas (II), (IIIa), (IIIb), (I'a) or (I'b), in protected or unprotected form, were subjected, if it was desirable or necessary, to one or more of the following reaction: - removing the protection from the protected OH group or groups, - acylation/alkylation of the OH group or groups, - the action of HNR3R4, optionally in salt form, when RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH. - salification. 8. Postupak priprave prema zahtjevu 7 spojeva prikazanih općom formulom (I) kao što su definirani u zahtjevu 2 kod kojih X predstavlja atom fluora na položaju 17 alfa i crtkane linije ne predstavljaju dvostruku vezu, naznačen time, da je halogenirajući reagens perfluoro-1-butan-sulfonil-fluorid (FSO2C4F9).8. The preparation process according to claim 7 of the compounds shown by the general formula (I) as defined in claim 2 where X represents a fluorine atom at position 17 alpha and dashed lines do not represent a double bond, indicated by the fact that the halogenating reagent is perfluoro-1- butane-sulfonyl-fluoride (FSO2C4F9). 9. Spojevi prikazani općom formulom (I) kao što je definirano u zahtjevu 1, kao i njihove soli s farmaceutski prihvatljivim kiselinama i bazama, naznačeni time, da se koriste kao lijekovi.9. Compounds represented by the general formula (I) as defined in claim 1, as well as their salts with pharmaceutically acceptable acids and bases, indicated to be used as medicines. 10. Spojevi prikazani općom formulom (I) kao što je definirano u bilo kojem od zahtjeva 2 do 3, kao i njihove soli s farmaceutski prihvatljivim kiselinama, naznačeni time, da se koriste kao lijekovi.10. Compounds represented by the general formula (I) as defined in any one of claims 2 to 3, as well as their salts with pharmaceutically acceptable acids, indicated to be used as medicines. 11. Spojevi kao što su definirani u zahtjevu 6, kao i njihove soli s farmaceutski prihvatljivim kiselinama, naznačeni time, da se koriste kao lijekovi.11. Compounds as defined in claim 6, as well as their salts with pharmaceutically acceptable acids, indicated to be used as medicines. 12. Farmaceutske kompozicije, naznačene time, da obuhvaćaju jedan ili više lijekova kao što su definirani u zahtjevima 9, 10 ili 11.12. Pharmaceutical compositions, characterized in that they include one or more drugs as defined in claims 9, 10 or 11. 13. Spojevi kao novi međuprodukti, naznačeni time, da su prikazani općim formulama (I’a), (IIIb) i (I’b) kao u zahtjevima 7 ili 8.13. Compounds as new intermediates, characterized by the fact that they are represented by the general formulas (I'a), (IIIb) and (I'b) as in claims 7 or 8. 14. Upotreba spojeva prikazanih općom formulom (I) kao što je definirano u zahtjevima 1 do 6, naznačena time, da je namijenjena pripravi lijekova za tretman hormonske zamjene kod menopauze ili perimenopauze, a koji imaju malu ili nikakvu aktivnost na nivou maternice.14. The use of compounds represented by the general formula (I) as defined in claims 1 to 6, indicated by the fact that it is intended for the preparation of drugs for the treatment of hormone replacement in menopause or perimenopause, which have little or no activity at the level of the uterus. 15. Upotreba prema zahtjevu 14, naznačena time, da su lijekovi namijenjeni za prevenciju ili tretman osteoporoze.15. Use according to claim 14, characterized in that the drugs are intended for the prevention or treatment of osteoporosis. 16. Lijek, kao što je definiran u zahtjevu 11, naznačen time da je namijenjen za prevenciju ili tretman osteoporoze.16. The drug, as defined in claim 11, characterized in that it is intended for the prevention or treatment of osteoporosis. 17. Lijek, kao što je definiran u zahtjevu 11, naznačen time da je namijenjen za kardiovaskularnu zaštitu.17. The drug, as defined in claim 11, characterized in that it is intended for cardiovascular protection.
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EA200100069A1 (en) 2001-06-25
FR2780060A1 (en) 1999-12-24
DE69906972D1 (en) 2003-05-22
PT1090027E (en) 2003-09-30
BR9912206A (en) 2001-04-10
MA26656A1 (en) 2004-12-20
JP2002518516A (en) 2002-06-25
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CN1313862A (en) 2001-09-19
IL140416A0 (en) 2002-02-10
JP4509380B2 (en) 2010-07-21
HUP0103194A3 (en) 2002-09-30
NO318381B1 (en) 2005-03-14
KR20010034919A (en) 2001-04-25
EP1090027A1 (en) 2001-04-11
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AP1579A (en) 2006-02-22
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AU771369B2 (en) 2004-03-18

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